This application is a 371 of PCT/EP00/08406 filed Aug. 28, 2000.
The invention is in the field of estrogenic compounds with a steroid skeleton having a non-aromatic A-ring and a free or capped hydroxyl group at carbon atom No. 3. Estrogenic compounds have a generally recognised utility in contraception and in the treatment of estrogen-deficiency related disorders, such as menopausal complaints, and osteoporosis.
Many estrogenic compounds are known. For example, an instructive publication on estrogenic compounds with a non-aromatic A-ring and a free or capped hydroxyl group at carbon atom 3 is U.S. Pat. No. 3,413,287. Other documents describing estrogenic or hormonal effects of non-aromatic streroids with 3-hydroxyl substitution and a 4-5 double bond are WO 94 18224, U.S. Pat. No. 3,465,010, FR 2099385, U.S. Pat. No. 3,652,606 and EP 145 493. A document in which non-aromatic steroids with 3-keto substitution and a 5-10 double bond are disclosed is Baran et al (U.S. Pat. No. 3,377,366. Such compounds are described in general terms as agents with, among other, estrogenic or anti-estrogenic effects. Recently, in the field of drugs for estrogen receptors (ER) attention is focussed on the discovery of two distinct types of estrogen receptors, denoted ERxcex1 and ERP (Mosselanan et al., FEBS Letters 392 (1996) 49-53 as well as EP-A-0 798 378). Since these receptors have a different distribution in human tissue, the finding of compounds which possess a selective affinity for either of the two is an important technical progress, making it possible to provide a more selective treatment of estrogen-deficiency related disorders, with a lower burden of estrogen-related side-effects.
This invention provides estrogens satisfying the general formula 
in which
R1 is H, (C1-C3)alkyl or (C2-C3)acyl;
R2 is H, xcex1-(C1-C4)alkyl, xcex1-(C2-C4)alkenyl or xcex1-(C2-C4)alkynyl;
R3 is H or (C1-C4)alkyl, (C2-C4)alkenyl or (C2-C4)alkynyl, each at location 15 or 16 of the steroid skeleton;
R4 is H or (C1-C5)alkyl, (C2-C5)alkenyl or (C2-C5)alknyl, each optionally substituted with halogen; preferred is ethynyl;
R5 is H, (C1-C3)alkyl or (C2-C3)acyl;
R6 is (C1-C5)alkyl, (C2-C5)alkenyl, (C2-C5)alkynyl or (C1-C5)alkylidene, each optionally substituted with halogen or (C1-C3)alkyloxy; allyl is preferred; preferred halogens in R6 are fluorine and chlorine.
Dotted bonds represent optional double bonds. When R6 is alkylidene, the dotted line to R6 represents the additional bond present in an alkylidene moiety, and when R6 is alkyl or alkenyl, the bond from atom 11 to R6 is a single bond.
It has been found that these non-aromatic estradiol derivatives with a substituent at the 11 position of the steroid skeleton possess selective affinity for the ERxcex1-receptor.
The compounds according to the present invention are suitable as improved estrogens, in the sense that they can be used in estrogen-related disorders, such as menopausal complaints and osteoporosis. Utility they also find in contraception, and they further may be suitable in the treatment or prevention of Alzheimer""s desease, breast tumor, benign prostate hypertrophy, and cardiovascular disorders. The compounds of the invention are particularly suitable in the treatment and prevention of estrogen-deficiency related disorders under diminished estrogen-related side-effects.
In this description terms have the following meaning:
(C1-C5)alkyl is a branched, unbranched or cyclized alkyl group having 1-5 carbon atoms, for example methyl, ethyl, isopropyl, 2-methylcyclopropyl, butyl, sec-butyl, tert-butyl etc.;
(C2-C5)alkenyl is a branched, unbranched or cyclized alkenyl group having 2 to 5 carbon atoms, such as ethenyl, 2-butenyl, etc.
(C2-C5)alkynyl is a branched or unbranched alkynyl group having 2-5 carbon atoms, such as ethynyl and propynyl.
(C2-C3)acyl is a group having 2-3 carbon atoms and derived from an alkylcarboxylic acid, the alkyl moiety having the meaning as defined previously.
(C1-C5)alkylidene is a branched, unbranched or cyclized alkylidene group having 1-5 carbon atoms, such as methylene and ethylene.
Within the general formula given above, the compounds of the invention preferably are those satisfying the general formula II, 
in which
R1 is H, (C1-C3)alkyl, (C2-C3)acyl;
R2 is H, xcex1-(C1-C4)alkyl, xcex1-(C2-C4)alkenyl, xcex1-(C2-C4)alkynyl;
R3 is H or (C1-C4)alkyl at location 16 of the steroid skeleton;
R4 is ethynyl
R5 is H or (C1-C3)alkyl, (C2-C3)acyl;
R6 is (C1-C5)alkyl, (C2-C5)alkenyl, (C2-C5)alkynyl; each can be substituted with chlorine or fluorine. When R6 is (C1-C2)alkyl, ethenyl or ethynyl, each optionally substituted with chlorine or fluorine, it is preferred that R3 is methyl at location 16 of the steroid skeleton.
More preferred are the steroids of the invention in which, in the above general formula II,
R1 is H;
R2 is H;
R3 is H or 16 xcex1-methyl;
R4 is ethynyl;
R5 is H;
R6 is propenyl, allyl or butenyl.
The compounds of the invention may be produced by various methods known in the art of organic chemistry in general, and especially in the art of the chemistry of steroids. See for example: Fried, J. and Edwards, J. A., xe2x80x9cOrganic Reactions in Steroid Chemistryxe2x80x9d, Volumes I and II, Van Nostrand Reinhold Company, N.Y., 1972; and C. Djerassi xe2x80x9cSteroid Reactionsxe2x80x9d, Holden-Day, Inc., San Francisco, 1963.
Synthesis of steroids with particular substituents at the C7 position are e.g. available via conjugate additions of organometallic species to appropriate 4,6-diene-3-one steroids, generally producing the 7xcex1 derived steroids (along with minor amounts of 7xcex2 steroids which can easily removed via crystallisation or chromatography. Many examples of which are known from literature. Introduction of substituents at the C11 position of the steroid skeleton can be performed in several ways. Conjugate addition of organometallic species to a suitably protected 5xcex1,10xcex1-epoxy, 9(11)-olefin as described by Teutsch et al, Steroids 37, 361 (1981) is such an approach, but other methods, using the 11-oxo functionality of an adequately protected 19-norandrost-5-ene as a reactive functionality for functional group interconversion to e.g. a C11-aldehyde according to well known chemical methodology (see a.o. E. Ottow et al., Tetr. Lett., 5253 (1993)) may be used as well to end up with claimed compounds. Of course a combination of both approaches outlined serves similarly well to achieve the goals. Introduction of a double bond at the 5(10) position is accomplished either by application of the so-called Birch reduction of the A ring of aromatic counterparts of suitably functionalized steroids, by dissolving metal reduction of xcex94-4,5-9,11-dienones, or by ketalization of 3-keto-xcex94-4,5-steroids. This latter procedure leads either directly to the desired selective xcex94-5(10)-isomers or leads to mixtures of ketals which can be separated via chromatography or crystallization at appropriate stages of the synthesis. Careful hydrolysis of the ketal at C3 generally affords the desired 3-oxo-xcex94-5(10)-isomers, which can be converted into the 3-OH compounds by hydride reductions. Saturated steroids (i.e. 5xcex1H-derivatives ) are easily available under reductive conditions like dissolving alkali metals in amines or ammonia. Introduction of double bonds at C14,15 is generally performed by firstly introducing a double bond at the C15,C16 position, followed by isomerization of this bond to the C14,C15 position according to well known procedures. The double bond introduced at C15,C16 may alternatively be used to perform a conjugate addition with e.g. cyanide, to allow the further construction of substituents at C15. The introduction of C16 substitution is easily performed by alkylation with appropriate bases and electrophiles.
The present invention also relates to a pharmaceutical composition comprising the steroid compound according to the invention mixed with a pharmaceutically acceptable auxiliary, such as described in the standard reference Gennaro et al., Remington""s Pharmaceutical Sciences, (18th ed., Mack publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture.). The mixture of the steroid compounds according to the invention and the pharmaceutically acceptable auxiliary may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories. By means of pharmaceutically suitable liquids the compounds can also be applied as an injection preparation in the form of a solution, suspension, emulsion, or as a spray, e.g. nasal spray. For making dosage units, e.g. tablets, the use of conventional additives such as fillers, colorants. polymeric binders and the like is contemplated. In general any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used. The steroid compounds of the invention may also be included in an implant, a vaginal ring, a patch, a gel, and any other preparation for sustained release.
Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof used in suitable amounts.
Furthermore, the invention relates to the use of the steroid compound according to the invention for the manufacture of a medicament in the treatment of estrogen-deficiency related disorders such as peri- and/or post-menopausal complaints. Thus the invention also pertains to the medical indications of peri- and/or post-menopausal (climacteric) complaints and osteoporosis, i.e. a method of treatment in the field of HRT (hormone replacement therapy), comprising the administration to a patient, being a woman, of a compound as described hereinbefore (in a suitable pharmaceutical dosage form).
Further, the invention relates to the use of the steroid compound according to the invention in the manufacture of a medicament having contraceptive activity. Thus the invention also pertains to the medical indication of contraception, i.e. a method of contraception comprising the administration to a subject, being a woman or a female animal, of a progestogen and an estrogen as is customary in the field, wherein the estrogen is a compound as described hereinbefore (in a suitable pharmaceutical dosage form).
Finally the invention relates to the use of the steroid compound for the manufacture of a medicament having selective estrogenic activity, such a medicament being generally suitable in the area of HRT (hormone replacement therapy).
The dosage amounts of the present steroids will be of the normal range for estradiol derivatives, e.g. of the order of 0.01 to 10 mg per administration.